1,2,4-Triazole Conjugates as HEGFR Inhibitors: Synthesis, Anticancer Evaluation, and in Silico Studies

Abstract

A series of novel 1,2,4-triazole-acetamide derivatives was synthesized and evaluated for anticancer and hEGFR inhibitory activity. The compounds were obtained via multistep synthesis and characterized by spectroscopic methods. Cytotoxicity was tested against PC-3, MCF-7, A549, and K562 cell lines. Compounds 18, 19, and especially 24 showed notable antiproliferative effects, with compound 24 exhibiting higher selectivity and potency than gefitinib. It also induced apoptosis and inhibited migration in A549 and PC-3 cells, while selectively promoting invasion in PC-3, suggesting EMT-related behavior. In vitro kinase assays revealed compound 20 as the most potent hEGFR inhibitor (IC<inf>50</inf> = 43.8 ± 1.3 nM). Molecular docking and 200 ns molecular dynamics simulations confirmed its stable interaction with EGFR, particularly involving Cys797. These findings highlight compounds 20 and 24 as promising candidates for further development as EGFR-targeted anticancer agents. © 2026 Wiley-VHCA AG.